Dysbetalipoproteinemia 

Dysbetalipoproteinemia, also called remnant removal disease, is a rare lipid disorder characterized by high levels of blood cholesterol and triglycerides.{Ref1} Cholesterol levels usually range from 300-600 mg/dL. Triglyceride concentrations are usually greater than 400 mg/dL and may exceed 1000 mg/dL. The disorder presents because of a decreased ability to convert very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) to low-density lipoprotein (LDL) particles in the blood and because of a decreased clearance of chylomicron remnants.

Dysbetalipoproteinemia is the result of 2 "hits". Most affected individuals are homozygous for the apolipoprotein E isoform, apoE2. The second "hit" is usually a metabolic disorder such as diabetes, obesity or hypothyroidism. Individuals who are homozygous for apoE2 have a 1-2% risk of developing the dysbetalipoproteinemia; and those who do are at high risk for atherosclerotic cardiovascular and peripheral vascular disease. The condition responds well to treatment of the causitive medical condition and to lipid-lowering medications.

VLDL is synthesized by the liver and is metabolized by lipoprotein lipase to IDL, also called VLDL remnants. Lipoprotein lipase hydrolyzes triglycerides releasing free fatty acids, which are taken up by myocytes and hepatocytes. Some apoCs, phospholipids, and apoEs are lost, and triglycerides are transferred to high-density lipoprotein (HDL) cholesterol in exchange for cholesterol esters. IDL is, thus, cholesterol-enriched and triglyceride-poor compared to unmetabolized VLDL. The principal remaining apolipoproteins are apoEs and apoB100, the structural or transmembrane apolipoprotein. As IDL is metabolized by hepatic lipase to LDL, the remaining surface apolipoproteins are lost.^{[2, 3, 4]}

ApoEs are ligands that have greater affinity for the LDL receptor than does apoB100. The LDL receptor is, in fact, more accurately designated the B/E receptor. ApoE also binds with high affinity to the LDL receptor-related protein, which takes up chylomicron remnants, VLDL and IDL. In addition, ApoE binds to cell-surface heparan sulfate proteoglycans (HSPG), which assists in the hepatic uptake of remnant lipoproteins.^[3]

The apolipoprotein E gene has been cloned, sequenced, and mapped to chromosome 19. Genetically altered apoE–deficient mice develop severe dyslipidemia with accelerated atherosclerosis, while transgenic mice overexpressing apoE appear to be protected from atherosclerosis.

ApoE has 3 isoforms that are present in slightly varying proportions, depending on race and geographic location. ApoE3 is the most prevalent allele and for that reason was considered the “wild type” allele from which apoE2 and apoE4 were derived. Newer data, however, suggests that apoA4 was the earliest form of the protein.

Most animals, including primates, possess an apoE4 equivalent.^[1] Compared with apoE3, apoE2 has less affinity for the receptor, and apoE4 has more. The alleles differ in 2 amino acid positions, 112 and 158. ApoE2 is most commonly caused by cysteine substituted for arginine at position 158 in apoE3. In apoE4, an arginine is substituted for cysteine at position 112 in apoE3. The substitutions are recessive in that dysbetalipoproteinemia requires the presence of 2 apoE-2 isoforms. Other very rare genetic variants of apolipoprotein E exist, and several of these have been shown to have defective binding to the LDL receptor and LDL receptor-like protein. These variants act in a dominant fashion in that only one copy of apoE is necessary for susceptibility to development of type III hyperlipidemia.

In Caucasian populations, approximately 1% of these individuals is homozygous for apoE2; however, only 10% of those will develop the condition. A “second hit” is necessary, most commonly metabolic abnormalities that cause increases in VLDL, including obesity, diabetes mellitus, or hypothyroidism. Other, less common genetic conditions can also predispose people to dysbetalipoproteinemia.

More than 90% of patients with dysbetalipoproteinemia are homozygous for apoE2; the remainder have a rare, usually dominant, defect in apoE2. In addition to the apoE2 homology or defect, and combined with a metabolic condition, other genetic factors have been suggested that increase the likelihood of developing dysbetalipoproteinemia. Polymorphisms in the apoA5, lipoprotein lipase and apoC3 have all been mentioned as possible cofactors for the condition.^[2]

Accumulation of IDL is caused by the poor affinity of apoE2 to LDL receptors, whereas LDL uptake via apoB100 is unaffected. In fact, total cholesterol, LDL cholesterol, and apoB are usually low compared with those with apoE3. Three mechanisms have been postulated for the hypocholesterolemic effect of apoE2:

• Increased upregulation of LDL receptors due to decreased binding of lipoproteins containing apoE2.
• Increased hepatic LDL uptake due to lower LDL receptor affinity of apoE2 and consequent decreased competition with the apoB100 born by LDL (its sole apolipoprotein).
• ApoE2 interference with lipolysis of VLDL to LDL^[3]

HDL cholesterol levels may be normal or decreased.

Frequency

United States

In the United States, the frequency of the alleles for apoE2, apoE3, and apoE4 in Caucasians is 13%, 76%, and 11%, respectively. In African Americans, the frequencies are approximately 12%, 65%, and 23%, respectively. The frequency of homology for apoE2 is 1.3%, but because of the necessary "second hit," only about 5% of homologous individuals have overt hyperlipidemia. The frequency of dysbetalipoproteinemia is less than 5 persons per 5,000 in the overall population.^[1]

International

The frequency of all 3 major apoE alleles varies by racial group. The incidence of the apoE2 allele, however, is always far lower than that of the apoE3 allele. Frequencies as low as 4.1% and 4.6% were found in Finland and in Singhalese of Indian descent, respectively. In addition to the United States, the highest frequencies were found in New Zealand (12.0%) and in Malaysian Singhalese (11.4%). Frequencies in other populations ranged from 6.1% (Iceland) to 9.7 (Chinese Singhalese).^[1]

Mortality/Morbidity

• Patients are at increased risk for premature cardiovascular disease and peripheral vascular disease.
• Patients with triglyceride concentrations substantially greater than 1000 mg/dL are at increased risk for acute pancreatitis.
• Normalizing blood lipids decreases the risk of developing atherosclerosis or pancreatitis.

Race

As noted above, the frequency of apoE2 varies somewhat by race, but the prevalence of dysbetalipoproteinemia appears to be similar among races. The racial differences are a consequence not only of apoE2 frequency, but also of the prevalence of the metabolic abnormalities necessary to cause dysbetalipoproteinemia.

Sex

• It is more common in men than in women.
• It is very rare in premenopausal women.
• Estrogen improves the clearance of VLDL remnants, and estrogen treatment appears to improve dysbetalipoproteinemia in some postmenopausal women.

Age

Dysbetalipoproteinemia primarily affects older adults and is rare in children and premenopausal women. However, in the United States and some other Western populations, the increasing incidence of childhood obesity and type 2 diabetes may presage the emergence of dysbetalipoproteinemia in children.